The safety of HIV pre-exposure prophylaxis in the presence of hepatitis B infection Marc M. Solomon, Mauro Schechter, Albert Y. Liu, Vanessa McMahan, Juan V. Guanira, Robert J. Hance, Suwat Chariyalertsak, Kenneth Mayer, Robert M Grant, for the iPrEx study team. Sponsored by NIH/NIAID/DAIDS and drug donated by Gilead Sciences

Marc Solomon, MD IAS/ANRS Lange-Van Tongeren Prize 2015

4 Background Oral FTC/TDF, or TDF, prevent HIV acquisition, 1-4 and are active against HBV. Withdrawal of anti-HBV medications, or the emergence of drug resistance, may allow HBV rebound, which may cause acute on chronic hepatic injury (or flare). 5-6 ▫ The risk of hepatitis flare is lower with lower pre-treatment clinical stage. 7 ▫ HBV resistance to TDF has not been documented. 8 ▫ There were no HBV flares after withdrawing TDF PrEP among 23 women with HBsAg and normal AST and ALT at enrollment. 9 ▫ HBsAg+ persons were excluded from other PrEP trials. The iPrEx study 1 included people with HBsAg+ at enrollment. 1. Grant NEJM 2010; 2. Baeten NEJM 2012; 3. Thigpen NEJM 2012; 4. Choopanya Lancet 2013; 5. Bessesen Clin Infect Dis (5):1032-5; 6. Mondou Clin Infect Dis (5):e45-7; 7. Thio Clin Infect Dis (7): Matthews Clin Infect Dis 2013;56(9):e87– Peterson PLoS Clin Trials 2007;2(5):e27. Solomon IAS Vancouver 2015

5 Lima Iquitos Guayaquil Sao Paulo Rio de Janeiro Boston San Francisco Cape Town Chiang Mai Solomon IAS Vancouver 2015 Sites11 Total Screened4459 Total Enrolled2499 iPrEx RCT Study Sites

6 Methods Inclusion / Exclusion for iPrEx. ▫ MSM and TGW reporting HIV risk factors. ▫ AST and ALT <2 x ULN. ▫ Total Bilirubin normal or near normal. ▫ Anti-HBc IgM negative. HBV serologies at screening: anti-HBs, anti-HBc, HBsAg. If HBsAg+ or isolated anti-HBc+. ▫ HBV DNA (after visits were completed). ▫ HBeAg and anti-HBe were tested. HBV susceptible people were offered HBV vaccine. HBsAg+ participants had extended followup. ▫ At 4, 8 and 12 weeks after stopping PrEP. Solomon IAS Vancouver 2015

7 Screening HBV serostatus Solomon IAS Vancouver 2015 (isolated anti-HBc+; all were DNA-) (anti-HBc IgM+) 13 with chronic hepatitis B infection were enrolled: 6 were randomized to FTC/TDF, 7 were randomized to placebo.

8 No hepatitis flare with PrEP gaps Solomon IAS Vancouver 2015 HBeAg-; anti-HBe+

9 No hepatitis flare with PrEP gaps Solomon IAS Vancouver 2015 HBeAg-; anti-HBe+

10 No hepatitis flare with PrEP gaps Solomon IAS Vancouver 2015 HBeAg-; anti-HBe+

11 No hepatitis flare with PrEP gaps Solomon IAS Vancouver 2015 HBeAg-; anti-HBe+

12 No hepatitis flare after stopping PrEP Solomon IAS Vancouver 2015 HBeAg-; anti-HBe+

13 No hepatitis flare after stopping PrEP Solomon IAS Vancouver 2015 HBeAg+; anti-HBe-

14 Acute HBV Infection on FTC/TDF PrEP 25 year old ▫ Starting FTC/TDF PrEP  Normal LFTs  Negative serologies  HBV DNA 30,684 ▫ 4 weeks of PrEP  AST 205, ALT 669  HBsAg-, anti-HBs-,  anti-HBc IgM+ ▫ 6 weeks of PrEP  LFTs normal ▫ 28 weeks of PrEP  Anti-HBs+, anti-HBc+  HBV immunity 35 year old ▫ Screening  Normal LFTs,  sAg+, eAg+, anti-HBc IgM- ▫ Started PrEP (14d later)  AST 214, ALT 304 ▫ 8 days on FTC/TDF  AST 1473, ALT 1061,  sAg+, eAg+, anti-HBc IgM+  Stopped FTC/TDF ▫ 12 weeks on study  Normal AST/ALT  Restarted FTC/TDF ▫ 28 and 72 weeks on FTC/TDF  Normal AST/ALT  sAg-, eAg-, eAb+, DNA- Solomon IAS Vancouver 2015

15 Vaccine Acceptance and Response Solomon IAS Vancouver 2015 Vaccine Uptake ▫ 1633 were eligible for Hep. B immunization ▫ 1587 (97.2%) received at least one dose ▫ 1383 (84.7%) received all three doses Vaccine Response Hep B Vaccine Doses Received % Immune (anti-HBs+) N immune / N evaluated 386.9%1021/ %38/ %12/27

16 Conclusions Regarding HBV and PrEP HBV vaccination rates are low, despite WHO recommendations. ▫ HBV vaccination uptake was high when offered free of charge. With isolated anti-HBc+ (anti-HBs-, HBsAg-). ▫ Was relatively common (5.5%). ▫ None had detectable HBV DNA. ▫ No hepatitis flare during and after FTC/TDF PrEP use. With HBsAg+ … ▫ Viral rebound but no clinical relapses during and after PrEP use. ▫ No TDF or FTC drug resistance during or after PrEP use. Acute HBV infection resolved to immunity in 2 starting FTC/TDF PrEP. Solomon IAS Vancouver 2015

17 Implications PrEP provides an opportunity to offer Hepatitis B vaccination. The HBsAg+ persons with normal or near normal AST and ALT have a very low risk of hepatitis B flare when stopping HBV active medications. HBsAg screening delays PrEP initiation and provides unclear safety benefits. Solomon IAS Vancouver 2015

This work was made possible by the participants and their communities who believed that research could improve their lives